Methylphenidate hydrochloride is a psychostimulant of phenethylamine class. The drug is safe, effective and approved for the treatment of attention-deficit hyperactivity disorder (ADHD), postural orthostatic tachycardia syndrome and narcolepsy in human. Long-term treatment with methylphenidate hydrochloride increases the activity of central nervous system, reduces the structural and functional abnormalities in the brain.
Dexmethylphenidate, also known as d-threo-methylphenidate (D-TMP) is a dextrorotatory enantiomer of methylphenidate, which is also effective psychostimulant against ADHD. Dexmethylphenidate is the (R,R) enantiomer of methylphenidate.
Racemic methylphenidate contains both dextro- and levo-rotatory methylphenidate, which are useful for the treatment of ADHD. It is very challenging to isolate a purified form of dexmethylphenidate.
Methylphenidate molecule contains two asymmetric centers and hence exists as four stereoisomers, two erythroisomers namely (R, S) and (S, R) and two threoisomers namely (R, R) and (S, S). Out of the four possible stereoisomers of methylphenidate, only threodiastereoisomers are used in modern practice. The eudysmic ratio between the threo (R, R) and (S, S) enantiomers of methylphenidate is high.
Different methods have been proposed in the state of art for the preparation of dexmethylphenidate hydrochloride using various chemical reactions and enzymatic resolution.
The United States patent numbered U.S. Ser. No. 09/204,460 titled “Process for preparing the d-threo isomer of methylphenidate hydrochloride” discloses a process for preparing the d-threo isomer of methylphenidate hydrochloride. The process involves the conversion of d,l-threo methylphenidate hydrochloride to a free base form, resolving the free base with (R)-(−)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate to obtain the phosphate salt enriched with the d-threo isomer of methylphenidate, basifying the phosphate salt to obtain the free base form of d-threo methylphenidate, converting the free base into the hydrochloride salt form of d-threo methylphenidate in high optical purity. Finally, the salt prepared is recrystallized to obtain the desired d-threo isomer with optical purity. However, the process may not result in high yield of the product and the invention is silent with respect to the recovery of the resolving agent.
The PCT application numbered PCT/GB1997/003418 titled “The preparation of enantiomerically-enriched threo-methylphenidate” discloses a process for increasing the enantiomeric excess of an enantiomerically-enriched mixture of enantiomers of an acid addition salt of threo-methylphenidate. The process involves crystallization followed by partial dissolution of methylphenidate. The process involves the bioresolution of racemic methylphenidate in presence of the enzyme that exhibits enantioselectivity. The enzyme used in the present invention is alpha-chymotrypsin. The enzymatic separation may involve specific reaction conditions to achieve good yield of the product and hence process may involve additional precautions to obtain optically pure compounds with high yield.
The United States patent numbered U.S. Ser. No. 09/063,100 titled “Process for preparing the d-threo isomer of methylphenidate hydrochloride” describes a process for preparing the d-threo isomer of methylphenidate hydrochloride comprising resolving the racemic mixture of threo methylphenidate hydrochloride with dibenzoyl-D-tartaric acid to obtain a dibenzoyl-D-tartrate salt enriched with the d-threo isomer of methylphenidate. The process involves the steps of resolving d,l-threo methylphenidate hydrochloride with 4-methylmorpholine and dibenzoyl-D-tartaric acid in the presence of dibenzoyl-D-tartrate salt enriched with the d-threo isomer of methylphenidate to obtain a dibenzoyl-D-tartrate salt enriched with the d-threo isomer of methylphenidate. The salt is basified to form a free base of d-threo methylphenidate. The free base is converted into hydrochloride salt of d-threo methylphenidate with high optical purity. Finally, the d-threo methylphenidate hydrochloride is recrystallized to obtain the desired d-threo isomer. However, the process may not result in increased yield of the product.
The existing processes for preparation of dexmethylphenidate hydrochloride are associated with disadvantages of repeatability of the process as well as the enantiomeric purity of the isolated dexmethylphenidate hydrochloride. In addition, many of the processes lack good yield of the product. Hence, there is a need for a process to prepare dexmethylphenidate hydrochloride with high yield and high enantiomeric purity.